The present invention concerns quinolone derivatives, pharmaceutical formulations containing the same, and methods of use thereof as antimitotic and antitumor agents, particularly for the treatment of tumors such as breast cancer and ovarian cancer.
Microtubules are one of the most important subcellular targets for the development of anticancer chemotherapeutic compounds. Vinca alkaloids and taxoids are well-known examples of antimitotic agents that are widely used clinically to treat different cancers (E. Rowinsky et al., Pharmacol. and Ther. 1992, 52, 35-84; J. Verweij et al., Ann. Oncol. 1994, 5, 495-505). Colchicine (FIG. 1) is another well-known agent that inhibits microtubule assembly (S. Hastie, Pharm. and Ther. 1991, 51, 377-401; S. Hastie, Pharm. and Ther. 1991, 51, 377-401). Although colchicine has limited utility for cancer therapy, the drug has been an important tool in studies of microtubule structure and function. The vinca alkaloids, taxoids, and colchicine each interact with tubulin by a unique mechanism, probably involving distinct binding sites on the protein.
The synthesis and biological evaluation of a series of 2-phenyl-4-quinolones as antimitotic and antitumor agents has been reported (S. Kuo et al., J. Med. Chem. 1993, 36, 1146-1156; L. Li et al., J. Med. Chem. 1994, 37, 1126-1135; L. Li et al., J. Med. Chem. 1994, 37, 3400-3407). The compounds were evaluated in the National Cancer Institute""s 60 human tumor cell line (HTCL) in vitro screen and in a tubulin polymerization inhibition assay. Most compounds showed cytotoxicity in the HTCL screen, with GI50 values in the low micromolar to nanomolar concentration range. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization. SAR studies led to the discovery of 2xe2x80x2-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (Compound 1; FIG. 1) (L. Li et al., J. Med. Chem. 1994, 37, 1126-1135), which showed cytotoxicity with an average log G150 value of xe2x88x926.47 (log concentration which reduced cell growth by 50%) in the HTCL screen. Compound 1 was also an inhibitor of tubulin polymerization, with an IC50 value of 0.85 xcexcM. Compound 1 also demonstrated good in vivo activity against the OVCAR-3 ovarian cell line, prolonging the life span of mice bearing the tumor by 130%.
Accordingly, an object of the present invention is to develop additional compounds that can be used as antimitotic agents, antitumor agents, or both.
A first aspect of the present invention is, accordingly, a compound according to Formula I, or a pharmaceutically acceptable salt thereof: 
wherein:
R1 is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R2 is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R3 is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R4 is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H);
R5 is is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, hydroxy, halo, and amino (preferably H or lower alkyl; most preferably H); and
n is 0, 1, 2, 3 or 4 (it being understood that, when n is 0, then all positions are substituted by H).
Preferably F is substituted on the phenyl group at the ortho position, or multi-F substituted at the ortho and other positions, as in a compound of the structure: 
or a pharmaceutically acceptable salt thereof.
A second aspect of the present invention is a pharmaceutical formulation comprising or consisting essentially of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier (e.g., an aqueous carrier).
A third aspect of the present invention is a method for treating a tumor comprising administering to a subject in need of such treatment a treatment effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A fourth aspect of the present invention is a method of inhibiting cellular mitosis, comprising: contacting a cell with a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cellular mitosis.
A fifth aspect of the present invention is a compound according to Formula II, or a pharmaceutically acceptable salt thereof: 
wherein:
R1 is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, amino, and heterocyclic rings;
R2 is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, and amino (preferably H or loweralkyl; most preferably H);
R3 is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, and amino (preferably H or loweralkyl; most preferably H); and
R4 is selected from the group consisting of H, hydroxy, lower alkyl, lower alkoxy, halo, and amino (preferably H or loweralkyl; most preferably H).
Preferably F is substituted on the phenyl group at the ortho position, or multi-F substituted on the phenyl group at the ortho and other positions, as in a compound of the structure: 
or a pharmaceutically acceptable salt thereof.
A sixth aspect of the present invention is a pharmaceutical formulation comprising or consisting essentially of a compound according to Formula II, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier (e.g., an aqueous carrier).
A seventh aspect of the present invention is a method for treating a tumor comprising administering to a subject in need of such treatment a treatment effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof.
An eighth aspect of the present invention is a method of inhibiting cellular mitosis, comprising: contacting a cell with a compound of Formula II, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cellular mitosis.
The foregoing and other objects and aspects of the present invention are explained in detail in the drawings herein and the specification set forth below.